The Kell blood group is one of the major antigenic systems in human red cells. It is complex and currently 23 alloantigens are determined to be present on, or associated with Kell protein. S. Lee, "Molecular Basis of Kell Blood Group Phenotypes", Vox Sang. 1997, 73:1-11, provides a summary of the Kell blood group system and of the molecular basis for the different phenotypes.
Among the various Kell alloantigens, KEL1 (K) is the strongest immunogen and antibodies to KEL1 cause severe reactions when mismatched blood is transfused. Sensitization to KEL1, although most common because of mismatched blood transfusion, can also occur during incompatible pregnancies. About 0.1% of pregnant mothers have antibodies to KEL1. This is a medical problem since babies who have inherited KEL1 from the father, are at risk of hemolytic disease of the newborn (HDN) if the mothers have Kell antibodies. HDN, caused by Kell-related antibodies, is unlike that caused by anti-Rh(D). Anti-Rh(D) causes red cell hemolysis while Kell antibodies are thought to suppress erythropoiesis (Weiner, et al., "Decreased Fetal Erythropoiesis and Hemolysis in Kell Hemolytic Anemia", Am. J Obstet. Gynecol. 1996, 174:547-551). Unlike anti-Rh(D) there is little correlation between anti-Kell titers, bilirubin levels and the severity of HDN, and anemic babies do not have a corresponding reticulocytosis. An in vitro study which supports these clinical observations has been recently reported by Vaughan et al., "Inhibition of Erythroid Progenitor Cells by Anti-Kell Antibodies in Fetal Alloimmune Anemia", N. Engl. J. Med. 1998, 338:798-803. Vaughen et al. concluded that both monoclonal and naturally occurring anti-Kell antibodies inhibit the growth of Kell-positive erythroid progenitor cells grown from mononuclear cells. The inhibition was dependent on the dose of the antibodies. These findings suggest that suppression of erythropoiesis at the progenitor-cell level is an important mechanism of fetal anemia due to anti-Kell antibodies. The mechanisms by which Kell antibodies suppress erythropoiesis are not known.
The Kell cDNA has been cloned (Lee et al, "Molecular Cloning and Primary Structure of Kell Blood Group Protein", Proc. Natl. Acad. Sci. U.S.A. 1991, 88:6353-6357) and characterization has also been done of the organizations of the 19 exons of the KEL gene (Lee et al., "Organization of the Gene Encoding the Human Kell Blood Group Protein", Blood 1995, 85:1364-1370; Lee et al., "The Human Kell Blood Group Gene Maps to Chromosome 7q33 and This Expression is Restricted to Erythroid Cells", Blood 1993, 81:2804-2809).
Methods were designed to genotype fetal KEL1 (Lee et al., "Prenatal Diagnosis of Kell Blood Group Genotypes: KEL1 and KEL2", Am. J. Obstet. and Gynecol., 1996, 175:455-459. This prenatal diagnostic procedure is currently used commercially to genotype fetus at risk for hemolytic disease of the newborn (HDN). Spence et al, "Prenatal Determination of Genotypes Kell and Cellano in At-Risk Pregnancies", J. Reprod. Med. 1997, 42:353-357.
Women (KEL:-1,2) who have antibodies to KEL1 and have KEL1/2 partners have a 50% chance of carrying a KEL:1 baby who is at risk of fetal anemia. A diagnostic method for the differential determination of Kell genotype in a patient is described in U.S. Pat. No. 5,589,336 to Lee and Redman.
Endothelins are known to have a variety of biological activities such as vasoconstriction, vasodilation, cell proliferation and cell migration. (Mateo and de Artinano, "Highlights On Endothelins: A Review", Pharmacol. Rev. 1997, 36:339-351; C. Rosendorff, "Endothelin, Vascular Hypertrophy, And Hypertension", Cardiovasc. Drugs 1997, 10:795-802. Endothelins also have regulatory effects on certain cytokines such as IL-6 which is known to be one of many growth factors affecting hematopoiesis. McMillan et al., "Endothelin-1 Increases Intracellular Calcium In Human Monocytes And Causes Production of Interleukin-6", Crit. Care Med. 1995, 23:34-40; Agui et al., "Stimulation of Interleukin-6 Production By Endothelin In Rat Marrow-Derived Stromal Cells", Blood 1994, 84:2531-2538.
KEL gene products exhibit strong homology with neutral endopeptidase-24.11 (NEP) which is the prototype of a family of zinc metalloproteinases that also includes the endothelin-converting enzymes (ECE) and the product of the PEX gene, and which are also structurally related to the bacterial enzymes thermolysin and lactococcol endopeptidase. Turner and Tanzawa, "Mammalian Membrane Metallopeptidases: NEP, ECE, KELL and PEX" FASEB J. 1997, 11:355-364. Biologically active substrates for NEP includes enkephalins and the atrial natriuretic peptide family. ECE catalyzes the final step in the biosynthesis of the vasoconstrictor peptide, endothelin (ET). However, according to these authors, no enzymatic activity has yet been attributed to KELL proteins and they remain peptidases in search of a substrate.